scholarly journals The Landscape of AhR Regulators and Coregulators to Fine-Tune AhR Functions

2021 ◽  
Vol 22 (2) ◽  
pp. 757
Author(s):  
Marco Gargaro ◽  
Giulia Scalisi ◽  
Giorgia Manni ◽  
Giada Mondanelli ◽  
Ursula Grohmann ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activity ◽  
Current Knowledge ◽  
Cellular Responses ◽  
Cell Physiology ◽  
Tissue Microenvironment ◽  
Aryl Hydrocarbon ◽  
Gene Transcriptional Regulation ◽  
Exogenous Ligands ◽  
Fine Tune

The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates numerous cellular responses. Originally investigated in toxicology because of its ability to bind environmental contaminants, AhR has attracted enormous attention in the field of immunology in the last 20 years. In addition, the discovery of endogenous and plant-derived ligands points to AhR also having a crucial role in normal cell physiology. Thus, AhR is emerging as a promiscuous receptor that can mediate either toxic or physiologic effects upon sensing multiple exogenous and endogenous molecules. Within this scenario, several factors appear to contribute to the outcome of gene transcriptional regulation by AhR, including the nature of the ligand as such and its further metabolism by AhR-induced enzymes, the local tissue microenvironment, and the presence of coregulators or specific transcription factors in the cell. Here, we review the current knowledge on the array of transcription factors and coregulators that, by interacting with AhR, tune its transcriptional activity in response to endogenous and exogenous ligands.

scholarly journals The Mast Cell-Aryl Hydrocarbon Receptor Interplay at the Host-Microbe Interface

2018 ◽  
Vol 2018 ◽  
pp. 1-6
Author(s):  
Claudio Costantini ◽  
Giorgia Renga ◽  
Vasilis Oikonomou ◽  
Giuseppe Paolicelli ◽  
Monica Borghi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Current Knowledge ◽  
Cell Physiology ◽  
Effector Functions ◽  
Host Protection ◽  
Aryl Hydrocarbon ◽  
Environmental Agents ◽  
Sense And Respond

Mast cells are increasingly being recognized as crucial cells in the response of the organism to environmental agents. Interestingly, the ability of mast cells to sense and respond to external cues is modulated by the microenvironment that surrounds mast cells and influences their differentiation. The scenario that is emerging unveils a delicate equilibrium that balances the effector functions of mast cells to guarantee host protection without compromising tissue homeostasis. Among the environmental components able to mold mast cells and fine-tune their effector functions, the microorganisms that colonize the human body, collectively known as microbiome, certainly play a key role. Indeed, microorganisms can regulate not only the survival, recruitment, and maturation of mast cells but also their activity by setting the threshold required for the exploitation of their different effector functions. Herein, we summarize the current knowledge about the mechanisms underlying the ability of the microorganisms to regulate mast cell physiology and discuss potential deviations that result in pathological consequences. We will discuss the pivotal role of the aryl hydrocarbon receptor in sensing the environment and shaping mast cell adaptation at the host-microbe interface.

scholarly journals Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

2017 ◽  
Author(s):  
Laura D'Ignazio ◽  
Michael Batie ◽  
Sonia Rocha
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Light Chain ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Cellular Responses ◽  
Nuclear Factor ◽  
Kappa Light Chain ◽  
Light Chain Enhancer

Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of kappa-light-chain-enhancer of activated B cells (NF-кB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-кB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-кB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-кB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-кB crosstalk.

scholarly journals The Role of lncRNAs in the Stem Phenotype of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6374
Author(s):  
Jorge Melendez-Zajgla ◽  
Vilma Maldonado
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Negative Effects ◽  
Tissue Microenvironment ◽  
Non Coding Rnas

Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC).

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

scholarly journals Development and Carcinogenesis: Roles of GATA Factors in the Sympathoadrenal and Urogenital Systems

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 299
Author(s):  
Takashi Moriguchi
Keyword(s):  
Transcription Factors ◽  
Developmental Process ◽  
Current Knowledge ◽  
Gynecologic Cancers ◽  
Inherited Diseases ◽  
Gata Factors ◽  
Transcriptional Regulatory ◽  
Gata Family

The GATA family of transcription factors consists of six proteins (GATA1-6) that control a variety of physiological and pathological processes. In particular, GATA2 and GATA3 are coexpressed in a number of tissues, including in the urogenital and sympathoadrenal systems, in which both factors participate in the developmental process and tissue maintenance. Furthermore, accumulating studies have demonstrated that GATA2 and GATA3 are involved in distinct types of inherited diseases as well as carcinogenesis in diverse tissues. This review summarizes our current knowledge of how GATA2 and GATA3 participate in the transcriptional regulatory circuitry during the development of the sympathoadrenal and urogenital systems, and how their dysregulation results in the carcinogenesis of neuroblastoma, renal urothelial, and gynecologic cancers.

scholarly journals NOD-Like Receptors: Guards of Cellular Homeostasis Perturbation during Infection

2021 ◽  
Vol 22 (13) ◽  
pp. 6714
Author(s):  
Gang Pei ◽  
Anca Dorhoi
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Current Knowledge ◽  
Protein Translation ◽  
Innate Immune ◽  
Cellular Homeostasis ◽  
Translation Block ◽  
Cytoskeleton Disruption ◽  
Molecular Patterns ◽  
Fine Tune

The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.

scholarly journals Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zi Wang ◽  
Pan Wang ◽  
Yanan Li ◽  
Hongling Peng ◽  
Yu Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Hematological Malignancies ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Hematologic Disorders ◽  
Cell Lineages ◽  
Stage Of Development ◽  
Transcription Complexes ◽  
Insight Into

AbstractHematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system.

scholarly journals Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthieu Dos Santos ◽  
Stéphanie Backer ◽  
Benjamin Saintpierre ◽  
Brigitte Izac ◽  
Muriel Andrieu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcription Factors ◽  
Neuromuscular Junction ◽  
Heavy Chain ◽  
Transcriptional Activity ◽  
Rna Seq ◽  
Hybrid Fibers ◽  
Adult Mice ◽  
Single Nucleus

Abstract Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.

scholarly journals Coactivator PC4 Mediates AP-2 Transcriptional Activity and Suppresses ras-Induced Transformation Dependent on AP-2 Transcriptional Interference

1999 ◽  
Vol 19 (1) ◽  
pp. 899-908 ◽  
Author(s):  
Perry Kannan ◽  
Michael A. Tainsky
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Transcription Factors ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Suppressive Effect ◽  
Transcriptional Coactivator ◽  
Transcriptional Interference ◽  
Mechanism Of Inhibition ◽  
Teratocarcinoma Cells

ABSTRACT ras oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP-2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have previously shown that overexpression of AP-2 in nontumorigenic variants of PA-1 cells results in inhibition of AP-2 activity and induction of tumorigenicity similar to that caused by ras transformation of PA-1 cells. Evidence indicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we found that PC4 is a positive coactivator of AP-2 and can restore AP-2 activity in ras-transformed PA-1 cells. Relative to vector-transfected ras cell lines,ras cell lines stably transfected with and expressing the PC4 cDNA have a diminished growth rate and exhibit a loss of anchorage-independent growth, and they are unable to induce the formation of tumors in nude mice. These data suggest that a transcriptional coactivator, like a tumor suppressor, can have a growth-suppressive effect on cells. Our experiments are the first to show that ras oncogenes and oncogenic transcription factors can induce transformation through effects on the transcription machinery rather than through specific programs of gene expression.

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